IE63533B1 - 2-(2-hydroxy-3-phenoxypropylamino)-ethoxybenzene derivatives - Google Patents

Abstract

Compounds of formula (I), wherein R<1> is hydroxy or C1-10alkyl, and in vivo hydrolysable esters and salts thereof are described as agents for the treatment of obesity and related conditions. Processes for their preparation and intermediates are described.

Description

The present invention relates to 2-hydroxy-3phenoxypropylamino compounds and in particular to such compounds containing a phenylacetyl group and certain derivatives thereof. This invention further relates to processes and intermediates for their preparation, to their use in methods of therapy and to pharmaceutical compositions containing them. Administration of the compounds of this invention to varm-blooded animals provides a thermogenic effect, that is thermogenesis is stimulated and administration of the compounds is of use, for example, in the treatment of obesity and related conditions such as obesity associated vith mature onset diabetes.

UK Patent 1245148 claims compounds of the general formula: vherein Ra is hydrogen, halogen, or a lover alkyl, phenyl, lover alkoxy or phenyl substituted lover alkyl group; R^ is hydrogen or up to tvo halogen, lover alkyl or lover alkoxy substituents; Rc is an electron-vithdraving polar substituent vhich may include groups such as carboxy, lover alkoxycarbonyl, formyl, lover alkanoyl, carbamoyl, sulpho, sulphino, alkcxysulphonyl, alkoxysulphinyl, sulphamoyl, cyano, azido, nitro or trifluoromethyl or any such group separated from the phenyl ring by a methylene or ethylene group; R^ and Re each represent hydrogen or a lover alkyl group; R^ represents hydrogen or a lover alkyl, alkanoyl or benzyl group; either of the benzene rings A and B may be optionally substituted further by a -CH»CH-CH»CH- radical to form a naphthyl group; Σ is oxygen or sulphur; and either Y is oxygen, sulphur or sulphinyl, sulphonyl or imino group and n is 1, 2 or 3; or Y is a direct bond and n is 0,1,2,3 or 4; vherein the term lover menas up to 4 carbon atoms.

These compounds are described as having the ability to block the beta-adrenergic receptors and are stated to be useful in the curative or prophylactic treatment of cardiac disorders such as angina pectoris and cardiac arrhythmias and in the treatment of hypertension. Biological data are reported describing the cardiac effects of various compounds vithin the claims.

Ve have nov discovered a small class of compounds related to those of the above general formula vhich compounds, surprisingly, provide significant thermogenic effects at doses vhich cause relatively fev side-effects. It is understood that selectivity of thermogenic effect, for example lack of cardiac side-effects, is an important requirement for a useful therapeutic agent in the treatment of, for example, obesity and related conditions.

Compounds of the formula: R ^>-OCH2CH(OH)CH2NHCRRjCH20OCH2Z 2 3 in vhich R is hydrogen or fluoro, R and R are hydrogen or 4 C^ ^alkyl, Z is -CH2OH or a group -COR vherein R is hydroxy, NH2 or Cj ^alkoxy are knovn as thermogenic agents from EP-A-210849. formula vherein Accordingly the present invention provides a compound of the (I): OCH2CH (OH) CH2NHCH2CH2O~^~~^— OCHYOR1 (I) r1 is hydroxy or Cj_jQalkyl, or an in vivo hydrolysable ester or a pharmaceutically acceptable salt thereof.

In one aspect R1 is hydroxy. In another aspect R^ is for example methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl n-hexyl and n-heptyl. Preferably R1 is ^alkyl for example, methyl ethyl, n-propyl, isopropyl, n-butyl and n-hexyl.

A The compounds of the formula (I) are basic and may be isolated and used either in the form of the free base or of a pharmaceutically acceptable acid-addition salt thereof. In addition, compounds vherein R1 is hydroxy are amphoteric and may be used in the zvitterionic form, or as a pharmaceutically acceptable acid addition salt, or as a salt vith a base affording a pharmaceutically acceptable cation. Particular examples of pharmaceutically acceptable acidaddition salts include, for example, salts vith inorganic acids such as hydrohalides (especially hydrochlorides or hydrobromides), sulphates and phosphates, and salts vith organic acids such as succinates, citrates, lactates, tartrates, oxalates and salts derived from acidic vater-soluble polymers. Particular examples of salts vith bases affording a pharmaceutically acceptable cation Include, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium and magnesium salts, and ammonium salts and salts vith suitable organic bases such as triethanolamine.

In vivo hydrolysable esters may be formed at the carboxy group (-COOH) and/or at the hydroxy group (-0H). In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human or animal body to produce the parent hydroxy compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include the C^^alkyl esters. Suitable in vivo hydrolysable esters for hydroxy include the ^alkanoyl esters.

It vill be appreciated that the compounds of the formula (I) contain one or more asymmetric carbon atoms and can exist as optically active enantiomers or as optically inactive racemates. The present invention encompasses any enantiomer, racemate and/or (vhen tvo or more asymmetric carbon atoms are present) diastereoisomer, vhich vhen administered in a therapeutic amount provides a thermogenic effect in varm-blooded animals, it being veil knovn in the chemical art hov to prepare individual enantiomers, for example by resolution of the racemate or by stereospecific synthesis, and hov to determine the thermogenic properties, for example, using the standard tests described hereinafter. It is preferred that the compounds of the present invention are provided in the (S) absolute configuration at the -CB(OB)- group (under the Cahn-Prelog-Ingold rules) vhich generally corresponds to the laevorotatory optically active form (-) in this class of compounds.

Particular compounds of the present invention include: 4-( 2-( 2-hydroxy-3-phenoxypropylamino)ethoxy] phenylacetic acid, (S)-4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxyJphenylacetic acid, 1-( 4-( 2-(2-hydroxy-3-phenoxypropylamino)e thoxy) pheny l]propan-2-one, (5)-1-( 4-( 2-(2-hydroxy-3-phenoxypropylamino)e thoxy) phenyl ]propan-2-one, 1-( 4-( 2-( 2-hydroxy-3-phenoxypropylamino)ethoxy) phenyl ]butan-2-one, (S)-l-(4-( 2-(2-hydroxy-3-phenoxypropylamino)e thoxy )phenyl J butan-2-one, l-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]pentan-2-one, (S)-1-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenylJ pentan-2-one, l-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl)-3-methylbutan-2 -one, 1-( 4-( 2-(2-hydroxy-3-phenoxypropylamino)e thoxy) phenyl ]hexan-2-one, 1- (4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenylJ-4-methylpentan2- one, 1-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl Jheptan-2-one, 1-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl J octan-2-one and l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]nonan-2-one.

In order to use a compound of the present invention or an in vivo hydrolysable ester or pharmaceutically acceptable salt thereof for the therapeutic treatment of varm-blooded mammals including humans, in particular for treating obesity, it is normally formulated in accordance vith standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition vhich comprises a compound of the formula (I) or an in vivo hydrolysable ester or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of this invention may be administered in standard manner for example by oral or parenteral administration. For these purposes they may be formulated by means knovn to the art into the form of, for example, tablets, capsules, pills, povders, aqueous or oily solutions or suspensions, emulsions, and sterile injectable aqueous or oily solutions or suspensions.

In general compositions for oral administration are preferred.

The compositions may be obtained using standard excipients and procedures veil knovn in the art. A unit dose form such as a tablet or capsule vill usually contain, for example 0.1-250 mg of active ingredient. The compositions may also contain other active ingredients knovn for use in the treatment of obesity and related conditions, for example appetite suppressants, vitamins and hypoglycaemic agents.

In one aspect of the present invention, a compound of the formula (I) may be formulated for oral administration in a sustained (or delayed) release composition, for example a matrix tablet formulation comprising insoluble or svellable polymeric filler, or a coated spheroid formulation.

Vhen used to produce thermogenic effects in varm-blooded animals including man, a compound of the formula (I) or an in vivo hydrolysable ester or pharmaceutically acceptable salt thereof as appropriate, vill be administered so that a dose in the general range 0.002-20 mg/kg, and preferably in the range 0.02-10 mg/kg, is administered daily, given in a single dose or divided doses as necessary. Hovever, it vill be appreciated by those skilled in the art that dosage vill necessarily be varied as appropriate, depending on the severity of the condition under treatment and on the age and sex of the patient and according to knovn medical principles.

In addition the compounds of the present invention lover triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in combatting medical conditions vherein such lovering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hypertriglyceridaemia, hypercholesterolaemia and conditions of lov HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions.

Accordingly in another aspect the present invention provides a method of lovering triglyceride and/or cholesterol levels and/or Increasing high density lipoprotein levels vhich comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or in vivo hydrolysable ester or pharmaceutically acceptable salt thereof. In a further aspect the present invention provides a method of treating atherosclerosis vhich comprises administering, to an animal in need thereof, a therapeutically effective amount of a compound of the formula (I) or in vivo hydrolysable ester or pharmaceutically acceptable salt thereof. The compositions are formulated and administered in the same general manner as detailed above for producing a thermogenic effect. They may also contain other active ingredients knovn for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin and pravastatin; inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA:cholesterol acyltransferase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, colestipol or a dialkylaminoalkyl derivatives of a cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics. β In a further aspect the present invention provides a process for preparing a compound of the formula (I) or an in vivo hydrolysable ester or a pharmaceutically acceptable salt thereof vhich process comprises: a) reacting a compound of the formula (11) or (III) vith a compound of the formula (IV): NH2CH2CH2O -CH2COR (Π) (HI) (IV) vherein R^ is as hereinbefore defined and L is a displaceable group; or b) hydrolysis of a compound of the formula (V): 7°^ cot (v) vherein R is as hereinbefore defined; or c) for compounds of the formula (I) vherein R^ is hydroxy, hydrolysing a compound of the formula (VI): OCH2CH(OH)CH2NHCH2CH vherein Rz is a hydrolysable group; d) reacting a compound of the formula (VII) vith a compound of the formula (VIII): OCH2CB(OH)CH2NH2 (VII) L'CH2CH2 (VIII) vherein R is as hereinbefore defined and L' is a leaving group; or 10 e) deprotecting a compound of the formula (IX): 1 vherein R is a protected derivative of a group -COR : (IX) and if necessary thereafter forming an in vivo hydrolysable ester or a pharmaceutically acceptable salt. Ο The reaction betveen a compound of the formulae (II) or (III) and a compound of the formula (IV) may be performed in a suitable solvent for example an alcohol such as ethanol or propan-2-ol, at a temperature in the range for example 10°C to 110’C and most conveniently at or near the boiling-point of the reaction mixture. In the compound of the formula (III) L may be for example halogen such as chloro or bromo or sulphonyloxy such as toluenesulphonyloxy or methanesulphonyloxy.

The compounds of the formula (IV) are prepared in any convenient manner knovn to those skilled in the art. For example they may be conveniently prepared by reacting compound (X) vith a compound of the formula (XI): nh2ch2ch2oh (X) (XI) For example this reaction may be performed using the Mitsunobu reaction vith diethyl azodicarboxylate and triphenylphosphine. Desirably the amino function (and carboxy-function, if present) is protected during this reaction and subsequently deprotected in conventional manner. Examples of suitable protecting groups for the amino function include the phthaloyl and t-butoxycarbonyl groups. The compounds of the formula(XI) may be prepared according to the methods described in the Examples hereinafter.

The compound of the formula (V) may be hydrolysed to a compound of the formula (I) under conditions knovn in the beta-blocker art; for example via alkaline hydrolysis in a suitable solvent.

The compounds of the formula (V) may be prepared by the reaction of a compound of the formula (XI) vith a compound of the formula (XII): A vherein R is a group -CH2CH2OH. This reaction may be performed in any conventional manner for example by a method analogous to the reaction of the compounds of the formulae (X) and (XI). In an alternative the compounds of the formula (V) may be prepared by the A reaction of a compound of the formula (XII) vherein R is hydrogen vith a compound of the formula (VIII) as hereinbefore described. In a further alternative the compounds of the formula (V) may be prepared by the reaction of a compound of the formula (II) vith a compound of the formula (XIII): R OCNHCH2CB2O ch2cor (ΧΠΙ) vherein R^ is as hereinbefore defined and R^O- is a leaving group, for example R^O- is ^alkoxy.

A The compound of the formula (XII) vherein R is -CH2CH2OH may be prepared for example by reaction of a compound of the formula (II) vith an N-alkoxycarbonyl derivative of a compound of the formula (X) vherein the hydroxy group is optionally protected, for example the tetrahydropyranyl ether of t-butoxycarbonylaminoethanol. The compounds of the formula (XII) vherein R is hydrogen are obtainable in conventional manner. The compounds of the formulae (VIII) and (XIII) may be obtained by alkylation of the compounds of the formula (XI) in conventional manner.

The reaction betveen the compounds of the formulae (VII) and (VIII) is conveniently performed under conditions analogous to the reaction betveen compounds of the formulae (III) and (IV). L' may have similar values as recited hereinabove for L.

In the compounds of the formula (VI) examples of 2 hydrolysable groups R include C. , alkoxy and -Nik groups so that -COR represents a Cj_6alkyl ester or primary amide function. Such groups may be hydrolysed (acidic, basic, enzymatic) to a group -CO^B under conventional conditions. Suitable acid conditions are for example a strong mineral acid such as hydrochloric, sulphuric or phosphoric acid, conveniently at a temperature in the range, for example, 20’ to 110’C and in a polar solvent, such as vater, a Cj ^alkanol (for example methanol or ethanol) or acetic acid. In such cases, the corresponding mineral acid salt of the compound of formula (I) vherein R^ is hydroxy may be conveniently isolated.

Alternatively, base conditions may be used, for example lithium, sodium or potassium hydroxide, conveniently in a suitable solvent or diluent such as an aqueous Cj^alkanol at a temperature in the range, for example, 10’ to 110’C; or an alkali halide for example lithium chloride in a polar solvent such as dimethylsulphoxide. As yet 2 further alternatives, vhen -COR is t-butoxycarbonyl, the decomposition may be carried out, for example, by thermolysis at a temperature in the range, for example, 100 to 220’C, alone or in the presence of a suitable diluent such as diphenyl ether.

The compounds of the formula (VI) may be prepared by methods analogous to those described hereinabove for the compounds of the formula (I), vith optional protection of the amino function for example vith a benzyl group.

Compounds of the formula (VI) also provide a thermogenic effect, in particular compounds of the formula (VI) vherein R is -NHj. Accordingly in another aspect the present invention provides compounds of the formula (VI), their use in methods of therapy (in particular in the treatment of obesity and related conditions) and pharmaceutical compositions containing them. The compounds of the f formula (VI) are used and formulated in a manner analogous to that described for the compounds of the formula (I).

In the deprotection of a compound of the formula (IX) R may for example be an acetal such as 2-methyl-l,3-dioxolan-2-yl or 2-ethyl-l,3-dioxolan-2-yl. Such groups may be readily converted to a group -COR1 vherein R1 is alkyl by acid hydrolysis. The compounds of the formula (IX) may be prepared by methods analogous to those described herein for the preparation of the compounds of the formula (I).

Certain of the compounds of the formulae (IV) and (VIII) are novel. Therefore, in another aspect the present invention provides a compound of the formula (XIV): vherein Z is amino, protected amino or a leaving group such Is as halo or sulphonyloxy and R is Cj^alkyl.

In vivo hydrolysable esters may be prepared in conventional manner for example by reacting the carboxy group vith an alcohol. It vill also be realised by the skilled man that groups R 3 and R in formulae (VI) and (IX) respectively, may be in vivo hydrolysable.

Pharmaceutically acceptable salts may be prepared by reacting the compound of the formula (I) vith the appropriate acid in conventional manner. Alternatively vhen a hydrogen halide salt is required, it may conveniently be obtained by hydrogenation of the free base together vith a stoichiometric amount of the corresponding benzyl halide. ι Λ j -fl The following biological test methods, data and Examples serve to illustrate this invention.

The thermogenic effects of the compound of the formula (I) may be demonstrated using one or more of the following standard tests:(a) Rats are cold adapted by being placed in a cold environment (4*C) for 10 days in order to increase their capacity for thermogenesis. They are then transferred to a thermoneutral environment (29°C). Three hours later the core temperature is measured to determine a base-line reading and the test compound is administered sub-cutaneously or orally as a solution or suspension in 0.45X v/v aqueous sodium chloride, 0.25X v/v Polysorbate 80. After one hour, the core temperature is again measured. In this test, a compound vhich causes a statistically significant increase in the core temperature of about 0.3°C (or more) at a sub-cutaneous dose of 15 mg/kg (or less) is considered to be significantly active. The test acts as a model for the depressed thermogenesis vhich occurs during dieting. (b) Rats are cold adapted at 4°C for 4 days to increase their capacity for thermogenesis. They are then transferred to a varm environment of 23°C for 2 days. On the following day, a test compound is administered sub-cutaneously or orally as described in (a). Animals are sacrificed one hour later and the interscapular, brovn adipose tissue (BAT) pad is removed. BAT mitochondria are prepared by differential centrifugation and GDP binding is determined (Holloway et al., International Journal of Obesity, 1984, 8, 295) as a measure of thermogenic activation. Each test includes a control vhich is dosed vith the solution/suspension vehicle only and a positive control vhich is dosed vith isoprenaline (as its sulphate) at 1 mg/kg. Test compounds are routinely dosed at 0.1, 0.3, 1.0, 3.0, and 10 mg/kg and results expressed in terms of the effect on GDP binding produced by isoprenaline. Prom these results, a dose (Εϋ^θ) necessary to produce 50X of the isoprenaline effect is calculated by linear regression analysis. Compounds are considered active in this test if they cause a significant elevation in GDP binding as compared to controls. This test serves to indicate that the thermogenic effects observed in test (a) are mediated through an increase in effect on BAT rather than by some non-specific or toxic mechanism. (c) Rats are adapted to a thermoneutral environment (29’C) for 2 weeks in order to decrease their capacity for BAT mediated nonshivering thermogenesis. During the final 3 days the animals are trained to use an apparatus for measuring heart rate non-invasively via foot-pad electrodes connected to an ECG integrator giving a continuous read-out of heart rate. A test compound is administered sub-cutaneously or orally at the ΕΟ^θ determined in test (b), and heart rate is determined 15-30 minutes after dosing. The procedure is then repeated in subsequent tests using increasing multiples of the ED^q determined in test (b) until the heart rate (HR) reaches or exceeds 500 beats per minute, allowing the dose necessary to produce a heart rate of 500 beats per minute (ϋ^θθ dose) to be calculated.

The ratio of to Εϋ^θ in test (b) can be defined as the selectivity index (SI) and provides a measure of the selectivity of the compound for BAT as opposed to the cardiovascular system.

Compounds are considered to have significant selectivity vhich have an SI of >1. Non-selective compounds have an SI of <1 (for example isoprenaline - 0.06). (d) Rats are cold adapted at 4°C for four days to increase their capacity for thermogenesis. They are then transferred to a warm environment at 23eC for tvo days. On the folloving day, the basal metabolic rate of the animals is determined using a close-circuit oxygen consumption apparatus of the type described by Arundel et al., 1984, J. Appl. Physiol. Respirat. Environ. Exercise Physiol., 1984, 57 (5) 1591-1593. The rats are then dosed (orally or sub-cutaneously) vith test compound at about (10 mg/kg) as a solution or suspension in 0.45X v/v aqueous sodium chloride, 0.25X v/v Polysorbate 80. Metabolic rate is then determined for at least one hour after dosing. Compounds are considered active in this test if they cause a significant increase in metabolic rate as compared to control animals (Student's t test: p <0.5) dosed only the solution or suspension vehicle. 6 In the above tests, the compounds of the formula (I) in general produce effects of the following order without producing over toxicity:test (a): increase in core temperature of about 0.5°C (or more) following a sub-cutaneous dosage of <15 mgkg-1; test (b): sub-cutaneous or oral Εϋ^θ for GDP binding in BAT mitochondria of 0.01-10 rngkg'1; and test (c): show an SI of >50.

By way of illustration, the compound described in the accompanying Example 5, produced the following effects in the above tests:(b) sub-cutaneous (oral) ED^q 0.23mgkg-1; (c) Dsnn: > "E^g-1 (oral); SI >100 (oral). ^-1 75 -1 (d) 6.6 ml 02 min Rg’ at lmgkg p.o.

The invention vill nov be illustrated by the following Examples in vhich, unless otherwise stated: a) nuclear magnetic resonance (NHR) spectra were determined at 200HHz in d^-dimethylsulphoxide/d^-acetic acid as solvent unless othervise stated, using tetramethylsilane (TMS) as an internal standard and are expressed in delta values (parts per million) for protons relative to TMS, using conventional abbreviations to describe signal types. b) chromatography vas performed on Merck Kieselgel (Art 7736) (for Example 1) or Kieselgel (Art 9385; 230-400 Mesh) (for Examples 2 - 13) obtainable from E. Merck, Darmstadt, Federal Republic of Germany. c) where noted, solutions were taken to pH values as judged by moist indicator paper. d) evaporations vere carried out under reduced pressure using a rotary evaporator. e) melting-points are uncorrected.

Example 1 4-[2-(2-Hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid. 4-[2-(2-Hydroxy-3-phenoxypropylamino)ethoxy ]pheny lacetamide (0.3g) vas heated on the steam-bath for 4 hours in 2N HCI (10ml). The reaction mixture vas cooled and the solid collected by filtration.

The solid vas crystallised from aqueous acetone to give 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenylacetic acid as the hydrochloride (0.18g), m.p. 190»C; microanalysis: found C,59.6; H,6.3; N,3.6; C1.9.2X; required for ci9H24C1N05: C,59.8; H,6.3; N,3.7; C1,9.3X; NMR 3.10 (dd,lH, one H of -CH(OH)CH2NH); 3.20(m,lH, the other H of -CH(0H)CH2NH); 3.40(t,2H,NHCH2CH2); 3.51(s,2H,CH2COOH); 4.00(m,2H,0CH2CH(0H)-); 4.2-4.35(m,3H,-CH(0H)- and -OCH2CH2-); 5.87(d,lH,OH); 6.95-7.30(m,9H, aromatic H); 8.7-9.3(br,2H,NH2).

The starting material vas obtained as follovs: A mixture of 4-(2-N-benzylaminoethoxy)phenylacetamide (OLS 2135678) (3.38g), phenylglycidyl ether (1.79g) and ethanol (150ml) vas heated under reflux for 18 hours. The mixture vas cooled and the solvent evaporated under reduced pressure. The residue vas purified by dry, flash column chromatography. Elution vith 10X methanol in dichioromethane gave 4-[2-(N-benzyl-N-(2-hydroxy-3phenoxypropyl)amino)ethoxyIphenylacetamide as an oil (4.98g). This vas dissolved in methanol (70ml) and acetic acid (30ml). The solution obtained vas hydrogenated in the presence of 10X v/v palladium on carbon (0.5g) at about 20 bar and 60’C for 48 hours. The mixture vas cooled, filtered and the filtrate vas evaporated under reduced pressure. The residual oil vas dissolved in methanol and heated vith a solution of ether saturated vith hydrogen chloride. The precipitated solid vas crystallised from methanol to give 4-[2-(2-hydroxy-3- phenoxypropylamino)ethoxy)phenylacetamide hydrochloride (4.3g), m.p. 249’C; microanalysis: found C, 60.0; H, 6.6; N, 7.4; Cl, 9.3X; required for C^H^CIN^: C, 59.9; H, 6.6; N, 7.4; Cl, 9.3X. Ρ Example 2 1-[4-(2-(2-Hydroxy-3-phenoxypropylamino)ethoxy)phenyl]propan-2-one. 4-(2-Phthalimidoethoxy)phenylpropan-2-one (lOg) in ethanol (40ml) vas treated at O’C vith 40 vtX aqueous methylamine solution (10ml). The reaction mixture vas stirred for 45 minutes at room temperature, treated vith vater (20ml) and stirring vas continued for a further 45 minutes. Ethanol vas evaporated under reduced pressure and the residue vas basified vith 30X NaOH. Vater (100ml) vas added and the mixture extracted vith ethyl acetate (3 x 100ml). The combined organic extracts vere dried, evaporated to dryness and subjected to chromatography using methanol:ethyl acetate (30:70) as eluant.

The desired fractions vere combined, collected, evaporated and heated for 3 hours in propan-l-ol (100ml) vith an equimolar quantity of phenylglycidyl ether. The reaction solution vas evaporated to dryness under reduced pressure and the residue vas subjected to chromatography as before using 5X methanol in dichloromethane as eluant. The appropriate fraction vas crystallised f rom ethanol 1-[4-(2-(2-hydroxy-3-phenoxypropylami no)ethoxy)phenyl]propan-2-one m.p. 105-106’C; microanalysis: found C, 69.7; H, 7.2; N, 4.2X; required for C20H25NO4:C’ 70.0; H, 7.3; N, 4.IX; NMR (CDCl.^) 2.13(s,3H, CH3), 2.80-3.10(m,4H, C^NCHj), 3.62(s,2H,CH2), 3.97-4.12(m,5H, 0CH2, CH20 and CHOH), 6.83-7.32(m,9H, aromatic H).

The starting material vas obtained as follovs: A solution of 4-hydroxyphenylpropan-2-one (22.5g), N-(2hydroxyethyl)phthalimide (28.6g) and triphenylphosphine (38.5g) in tetrahydrofuran (IL) vas treated dropvise at -5’C vith diethyl azodicarboxylate (23ml). The reaction mixture vas stirred at room temperature overnight, evaporated to dryness and treated vith ether (500ml). The solution vas kept overnight at about 4°C and the solid vas collected and recrystallised from ethanol to give 4-(2phthal imi doethoxy)phenylpropan-2-one, m.p. 116-117°C; microanalysis: found C, 70.5; H, 5.4; Ν, 4.4X; required for C^gH^NO^: C, 70.6; H, 5.2; Ν, 4.3X.

Example 3 1- [ 4-( 2- (2-Hydroxy-3-phenoxypropylamino )e thoxy) phenyl ]propan-2-one. 1-(4-((2-Methyl-l,3-dioxolan-2-yl)methyl)phenoxy)-2-(ptoluenesulphonyloxy)ethane (lg) and l-phenoxy-3-aminopropan-2-ol (0.4g) vere heated at 65°C for 12 hours in dimethylsulphoxide (10ml). The cooled reaction mixture vas treated vith ice-cold 2N HCl (50ml) at ambient temperature for 1 hour. The mixture vas basified vith solid sodium carbonate and extracted vith ether (2 x 50ml). The combined ether extracts vere dried, evaporated to dryness and the residue treated vith a small volume of acetone to yield a solid, identical in all respects to the product of Example 2.

The starting-material vas obtained as follows: A solution of 2—(4—[(2-methyl-l,3-dioxolan-2yl)methylJphenoxyJethanol (EP-A-70133) (30g) in anhydrous pyridine (500ml) vas treated at 0eC vith p-toluenesulphonyl chloride (25g) in portions. The reaction mixture vas stirred at 0°C for 2 hours and at ambient temperature for 2 hours. Most of the pyridine vas evaporated under reduced pressure. Vater (1.5L) vas added, followed by sufficient saturated sodium hydrogen carbonate solution to take the pH of the solution to approximately 9. The mixture vas extracted vith ether (3 x 500ml) and the combined organic extracts vere vashed vith N HCl (100ml) and vith saturated sodium hydrogen carbonate solution (several times) until the extracts vere alkaline. The ether solution vas dried and evaporated to dryness to yield l-[4-((2-methyll, 3-dioxolan-2-yl)methyl)phenoxyJ-2-(p-toluenesulphonyloxy)ethane, m. p. 80°C (from ethanol); microanalysis: found: C, 61.0; H, 6.IX; required for C» 61.2; H, 6. IX. ° η Example 4 l-[4-(2-(2-Hydroxy-3-phenoxypropylamino)ethoxy)phenyl]butan-2-one 1-(2-(4-(2-Ethyl-l,3-dioxolan-2-ylmethyl)phenoxy)ethylamino] -3-phenoxypropan-2-ol (2.0g) in a mixture of methanol (38ml) and concentrated hydrochloric acid (38ml) vas stirred at 65eC for 1 1/2 hours. The reaction mixture vas cooled, poured into vater (120ml), basified vith sodium hydroxide solution and extracted into ethyl acetate (3 x 50ml). The ethyl acetate extracts vere vashed vith brine (2 x 50ml), dried and the solvent removed under reduced pressure. The residual solid vas converted to the hydrochloride and the salt crystallised from ethanol to yield vhite crystals of the title compound in the form of the hydrochloride (1.70g); m.p. 167-169eC; microanalysis: found C, 63.9; H, 7.2; Ν, 3.4X; required for C21H2gClNO4, C,64.0; H, 7.1; Ν, 3.6X; NMR O.93(t,3H,COCH2C|3), 2.48(q,2H,C0CH2CH3), 3.06-3.47(m,4H,CH2NHCH2), 3.68(s,2H,ArC|2C0), 3.92-4.O8(m,2H,PhOCH2CH), 4.22-4.38(m,3H,CHOH and C^CHjOAr), 6.88-7.35(m,9H, aromatic R).

The starting material vas prepared as follovs: a) l-(4-Hydroxyphenyl)butan-2-one vas prepared by the action of diethylcadmium on 4-methoxyphenylacetyl chloride in toluene folloved by demethylation in a mixture of hydrobromic acid and acetic acid as described by V R Biggerstaff et al. J. Med. Chem. 1964,7, 110-113. b) A solution of l-(4-hydroxyphenyl)butan-2-one (10.Og), 1,2ethanediol (7.5ml) and p-toluenesulphonic acid (lOOmg) in toluene (200ml) vas stirred under reflux in a Dean and Stark apparatus for 2 hours in an atmosphere of argon. The reaction mixture vas cooled, vashed vith 5X aqueous sodium bicarbonate (150ml), vashed vith vater (2 x 100ml), vashed vith brine (100ml) and dried. Toluene vas removed under reduced pressure and the residual oil triturated vith hexane to give a light brovn solid vhich vas crystallised from toluene to give 4-l(2-ethyl-l,3-dioxolan-2-yl)methylJphenol as vhite crystals (10.2g) m.p. 88-90’C; microanalysis: found C, 69,3; Η, 7.8X; required for C12H16°3: C’ 69,2; H’ 7’7Z‘ c) Diethyl azodicarboxylate (9.7ml) vas added dropvise to a stirred solution of 4-l(2-ethyl-l,3-dioxolan-2-yl)methyl)phenol 1 (10.Og), Ν-t-butoxycarbonylaminoethanol (13.3g) and triphenylphosphine (16.3g) in anhydrous tetrahydrofuran (300ml), at ice-bath temperature, under argon. The reaction mixture vas left for 64 hours at 20’C and then the solvent vas removed under reduced pressure. The residue vas dissolved in ether (600ml) and the ethereal solution vashed vith 2N aqueous sodium hydroxide (2 x 150ml), vater (2 x 100ml) and saturated brine (100ml). The aqueous washings vere in turn extracted vith ether (100ml). The ethereal solutions vere combined, dried, and the ether removed under reduced pressure. The residue vas purified by chromatography using 35X ethyl acetate in hexane as eluant. Combining the appropriate fractions and crystallisation from hexane yielded 1-tbutoxycarbonylamino-2-[4-(2-ethyl-l,3-dioxolan-2-yl)methylJphenoxy]ethane as vhite crystals (11.lg) m.p 64-66’C; microanalysis: found C, 65.4; H, 8.0; Ν, 4.2X; required for C^H^NO^: C, 65.0; H, 8.3; N 4.OX. d) The product from c) above (ll.Og) vas added to a stirred suspension of sodium hydride (1.50g of a 50X dispersion in mineral oil) in dry dimethylformamide (220ml) under argon. The reaction mixture vas stirred at 50°C for 1 1/2 hours. The mixture vas cooled to 0°C, phenylglycidyl ether (4.3ml) vas added and the reaction mixture then stirred at 50*C for 1 3/4 hours. The reaction mixture vas cooled, poured into vater (1.2L) and the product extracted into ethyl acetate (400ml, 250ml, 200ml). The combined ethyl acetate extracts vere vashed vith vater (500ml), dried and the solvent removed under reduced pressure. The residue vas purified by chromatography using 60X ethyl acetate in hexane as eluant. The appropriate fractions vere combined, evaporated and the residue triturated vith hexane to give a solid vhich vas crystallised from cyclohexane to give 3-(2(4-(2-ethyl-l,3-dioxolan-2-ylmethyl)phenoxy)ethyl )-5(phenoxymethyl)oxazolidin-2-one as vhite crystals (4.0g), m.p. 88-90eC; microanalysis: found C, 67.4; H, 7.0; Ν, 3.2X; required for C2Z,H29NO6: C, 67.4; H, 6.8; Ν, 3.3X. e) A solution of product from d) above (4.0g) in a mixture of 2N aqueous sodium hydroxide (12ml) and ethanol (60ml) vas heated under reflux under argon for 8 hours. The reaction mixture vas cooled, poured into vater (100ml) and the product extracted into dichloromethane (3 x 60ml). The combined extracts vere vashed vith ° brine (60ml), dried, and the solvent removed under reduced pressure. The residual solid vas crystallised from ethanol to yield 1-(2-(4-(2ethyl-1,3-dioxolan-2-ylmethyl)phenoxy)ethylamino(-3-phenoxypropan-2-ol as vhite crystals (3.0g) m.p. 101-103’C; microanalysis: found C, 69.1; H, 7.8; Ν, 3.4X; required for C23H31N05: C, 68.8; H,7.7; Ν, 3.5X.

Examples 5 and 6 In a manner similar to that of Example 4, the folloving compounds as the hydrochloride salts vere prepared from 1-(4hydroxyphenyl)pentan-2-one and 1-(4-hydroxyphenyl)-3-methylbutan-2-one respectively.

PhOCH2CH(OH)CH2NHCH2CH2O—// y—CH2COR Example | I I R | m.p. |(solvent) 1 | Hicroanalysis/NMR 1 1 5 I -CH2CH2CH3 1 165-7’C |Found: C, 64.9; H, 7.5; Ν, 3.3X; 15 I I I I 1 5 |(ethanol) 1 1 1 1 | required for C22B30C1NO4: C, 64.8; |H, 7.4; Ν, 3.4X; |NMR 0.83(t,3H,COCH2CH2CH3), |1.49(sextet, 2H, COCHjCHjCHj), |2.44(t,2H, C0CH2CH2CH3), 3.11- 20 1 1 1 1 1 1 1 1 1 1 1 1 |3.50(m,4H, CH2NHCH2), |3.67(s,2H, ArCH2C0-), 3.95|4.09(m,2H,Ph0CH2CH-), 4.22|4.38(m,3H.CHOH and CH2CH2OAr), |6.90-7.34(m,9H,aromatic H). 1 3 Example I R I | m.p. | (solvent) | Microanalysis/NMR I 6 1175-7eC |Found: C, 64.9; H, 7.4; Ν, 3.3X; I I | (ethanol) I |required for CjjHjoCINO^: C, 64.8 |H, 7.4; Ν, 3.4X; I I I I I I I I I I I I I I I I |NMR 1.05(d,6H,C0CB(CH3)2), |2.74(septet, IH, COCH(CH3)2), |3.18-3.54(m,4H,CH2NHCH2), |3.74(s,2H,ArCH2CO), 3.98|4.11(m,2H,PhOCH2CH-), 4.29|4.40(m,3H,CH0H and CHjCHjOAr), |6.90-7.34(m,9H, aromatic B). l For convenience the scheme for the preparation of the compounds of Examples 4-6 is set out below (vherein R is ethyl, n15 propyl or isopropyl). ο Λ Scheme 1 (2) HO——C Γ\ PhOCH2 0—^¢0 ΛΛ __„ o o \ ΑΛ \ / CH2CH2O-0 A-ch2-c-r ButOCONHCH2CH2 (4) (3) PhOCH2CH(OH)CH2NHCH2CH2 r\ 0 \ / h2-c-r (5) PhOCH2CH(OH)CH2NHCH2CH2 ch2cor (6) χ. ο Footnotes to scheme: A. l-(4-Hydroxyphenyl)pentan-2-one (compound(l): R -CHjCHjCBj) vas prepared as follovs: 1-Bromopropane (33·2ml) in anhydrous ether (100ml) vas added dropvise over 30 minutes to a stirred suspension of lithium slices (6.0g; 0.86 gm atoms) in ether (150ml) under argon, maintaining the internal temperature at 0° to -10°C. The reaction mixture vas stirred for 1 1/2 hours at 0-5’C and added to a stirred solution of 4hydroxyphenylacetic acid (5.6g) in anhydrous tetrahydrofuran (300ml) at 0 - 10’C under argon, leaving behind any unreacted lithium. The reaction mixture vas stirred for 40 hours at 22eC, then cooled in an ice-bath and chlorotrimethylsilane (50ml) vas added over 15 minutes. The temperature vas alloved to rise to 22*C. and the reaction mixture vas poured into IN hydrochloric acid (600ml) and stirred for 1/2 hour. The product vas extracted into ethyl acetate (3 x 200ml) and the combined extracts vashed vith aqueous sodium bicarbonate (2 x 300ml), vashed vith brine (100ml), dried and the solvent removed under reduced pressure. The procedure vas repeated three times on the same scale and the combined crude ketone vas purified by chromatography using 22X ethyl acetate in hexane as eluant. The appropriate fractions vere combined and evaporated to yield l-(4-hydroxyphenyl)pentan-2-one (3.4g) as a yellov oil. (A similar procedure for the preparation of methyl ketones is described by G M Rubottom and Chong-Van Kim, J.O.C. 1983, 48, 1550-1552).

B. l-(4-Hydroxyphenyl)-3-methylbutan-2-one (compound (1): R « -CH(CH3)2) vas prepared as follovs: A solution of isopropyl magnesium bromide (prepared from magnesium (1.75g) and 2-bromopropane (8.9g)) in dry tetrahydrofuran (100ml) vas added dropvise over 30 minutes to a stirred solution of 4methoxyphenylacetyl chloride (26.6g) in tetrahydrofuran (75ml) under argon, maintaining the internal temperature at -65’ to -70*C. The reaction mixture vas alloved to varm up to 20’C over 1 hour and then poured into vater (150ml). The product vas extracted into ether (2 x 70ml). The ether extracts vere vashed vith IN aqueous sodium hydroxide (2 x 70ml), brine (70ml), dried, and the solvent removed under reduced pressure. The residue vas purified by chromatography using 10X ethyl acetate in hexane as eluant. The appropriate fractions vere combined and the solvent removed under reduced pressure to yield l-(4-methoxyphenyl)-3-methylbutan-2-one (2.5g) an oil. l-(4-Methoxyphenyl)-3-methylbutan-2-one (10.2g) vas added to a stirred melt of pyridine hydrochloride (36ml) at 140"C under argon. The reaction mixture vas heated to 220°C for 2 hours. The mixture vas cooled, vater (400ml) vas added and the product extracted into ether (3 x 150ml). The combined ethereal extracts vere vashed vith brine (100ml), dried, and the solvent removed under reduced pressure. The residual oil vas purified by chromatography using 25X ethyl acetate in hexane as eluant. The appropriate fractions vere combined to give l-(4-hydroxyphenyl)-3-methylbutan-2-one (7.9g) as an oil.

C. Physical Data for Intermediates in the preparation of the compounds of Examples 5 and 6.

Example 5 Compound (2) Compound (3) Compound (4) Compound (5) m.p. (solvent) , Microanalysis 1 1 oil 1 80-2’C |Found C, 65.6; H, 8.6; Ν, 3.8X; required (cyclohexane) 1 for C2QH31NO5:C, 65.8; H, 8.5; Ν, 3.8X 90-1’C |Found C, 67.0; H, 7.1; Ν, 3.3X; required (cyclohexane) |for C25H31N06 1/2H2O:C, 66.7; H, 7.1; |N,3.IX 104-6’C |Found C, 69.4; H, 8.0; Ν, 3.2X; required (ethanol) 1 for C24N33N05:C, 69.4; H, 8.0; Ν, 3.4X 1 Example 6 | m.p. |(solvent) | Microanalysis 1 Compound (2) | 84-6’C |Found C, 70.8; Β, 8.5X; required for |(cyclohexane)|C13H18°3 C’ 70,3; H’ 8,1X Compound (3) | 113-5’C |Found C, 65.7; B, 8.5; Ν, 3.7X; required | (cyclohexane) |for C2QB31N05 C, 65.8; B, 8.5; Ν, 3.8X Compound (4) | 128-9’C |Found C, 67.6; B, 6.8; N, 3.IX; required |(toluene) |for C25B31N06 C, 68.0; B, 7.0; Ν, 3.2X Compound (5) | 98-100’C ,Found C, 69.2; B, 7.9; Ν, 3.3X; required |(ethanol) 1 |for C24B33N05 C, 69.4; B, 8.0; Ν, 3.4X 1 K«—ple 7 1—[4—(2-(2-Bydroxy-3-phenoxypropylamino)e thoxy)phenyl)bu tan-2-one.

A solution of 3-[2-(4-(2-oxobutyl)phenoxy)ethylJ-5(phenoxymethyl)oxazolidin-2-one (200mg) in hot ethanol (4al) vas treated vith 2N aqueous sodium hydroxide (0.75ml) and the reaction mixture vas stirred under reflux for 4 hours under argon. The reaction mixture vas cooled, poured into vater (20ml) and the product vas extracted into dichloromethane (3 x 20ml). The dichloromethane extracts vere vashed vith brine (20ml), dried, and the solvent vas removed under reduced pressure. The residue vas converted to the hydrochloride and crystallised from ethanol to yield the title compound in the form of the hydrochloride (150mg); m.p. 166-8eC.

The starting material vas prepared as follows: a) A solution of N-t-butoxycarbonylaminoethanol (2.0g), dihydropyran (1.7ml) and pyridinium p-toluenesulphonate (310mg) in anhydrous dichloromethane (90ml) vas stirred at room temperature for 2 1/2 hours. Ether (150ml) vas added, the solution vas vashed vith vater (2 x 50ml), dried, and the solvent removed under reduced pressure to give 2-(2-(N-t-butoxycarbonylamino)ethoxy)tetrahydropyran (3.0g) as a yellov oil. b) The product from a) above (2.9g) vas added to a stirred suspension of sodium hydride (570mg of a 50X dispersion in mineral oil, 0.012 moles) in anhydrous dimethylformamide (100ml) under argon.

The reaction mixture vas stirred at 55eC for 1 1/2 hours. The mixture vas cooled to 0°C, phenylglycidyl ether (1.6ml) vas added and the reaction mixture then stirred at 20’C for 2 1/2 hours. The reaction mixture vas poured into vater (500ml) and the product extracted into ethyl acetate (350ml, 100ml, 100ml). The combined ethyl acetate extracts vere vashed vith vater (200ml), dried, and the solvent removed under reduced pressure. The residue vas subjected to chromatography using 60X ethyl acetate in hexane as eluant. The appropriate fractions vere combined to yield -phenoxymethyl-3-(2-( tetrahydropyran-2-y loxy )e thyl )oxazolidin-2-one (l.Og) m.p. 78-80’C (cyclohexane); microanalysis: found C, 63.3; H, 7.2; Ν, 4.3X; required for ^|7^23^θ5: 63.6; H, 7.2; Ν, 4.4X. c) A solution of the product of b) above (0.88g) and pyridinium p-toluenesulphonate (70mg) in a mixture of vater (1.0ml) and ethanol (24ml) vas stirred at 65’C for 4 hours. Ethanol vas removed under reduced pressure and the residue partitioned betveen vater (30ml) and ethyl acetate (30ml). The organic layer vas separated and the aqueous layer re-extracted vith ethyl acetate. The ethyl acetate extracts vere vashed vith vater (20ml), dried, and the solvent removed under reduced pressure. Trituration of the residue vith ether folloved by crystallisation from propan-2-ol yielded 5-phenoxymethyl-3-(2- hydroxyethyl)oxazolidin-2-one (0.52g) m.p 89-91’C; microanalysis: found C, 60.8; B, 6.3; Ν, 5.8X; required for C12H15N04! C’ 6θ·8; H’ 6,3? N’ 5,9X· d) Diethyl azodicarboxylate (0.33ml) vas added dropvise to a stirred solution of l-(4-hydroxyphenyl)butan-2-one (0.35g), part of the product from c) above (0.50g) and triphenylphosphine (0.55g) in anhydrous tetrahydrofuran (13ml), at ice-bath temperature, under argon. The reaction mixture vas left for 100 hours at 20eC and then the solvent removed under reduced pressure. The residue vas dissolved in ethyl acetate and the solution seeded vith 1,2-dicarbethoxyhydrazine. The solution vas alloved to stand for 2 hours, the solid vas collected and the filtrate vas. subjected to chromatography using 50X ethyl acetate in hexane as eluant. The appropriate fractions vere combined, evaporated, and the residue vas crystallised from ethyl acetate/cyclohexane to give 9 3-(2-(4-(2-oxobutyl)phenoxy)ethyl]-5-(phenoxymethyl)oxazolidin-2-one (280mg); m.p 67-69eC; microanalysis found C, 68.9; H, 6.6; Ν, 3.7X; required for C, 68.9; H, 6.5; Ν, 3.7X.

Examples 8-12 In a manner similar to that of Example 7, the folloving compounds as the hydrochloride salts vere prepared from l-(4-hydroxy phenyl)hexane-2-one, l-(4-hydroxyphenyl)-4-methylpentan-2-one, l-(4-hydroxyphenyl)heptan-2-one, 1-(4-hydroxyphenyl)octan-2-one and l-(4-hydroxypheny1)nonan-2-one respectively.

Ph0CH2CH(0H)CH2NHCH2CH20 CH2C0R Ο Example I R1 1 1 1 ®·ρ· 1 | (solvent) ) 1 1 Microanalysis/NMR 8 1 -2)3ch3 1 1 1 1 1 1 1 1 1 1 1 1 | 173-5’C 1 | (ethanol)| 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Found: C,65.1; H,7.6; N,3.3X; required for C^H^CINO^: C,65.5; H. 7.6; Ν, 3.3X; NMR 0.84(t,3B, COCH2CH2CH2CH3) I. 23(sextet, 2H, COCB2CB2C|2CB3); 1.46(quintet, 2H, COCHjCHjCHjCB,/; 2.46(t,2B, COCH2CH2CB2CB3); 3.09-3.47(m,4B, CB2NHCB2); 3.68(s,2B,ArCB2C0); 3.95-4.09(m,2B,PhOCBjCB); 4.22-4.36(m,38,CHOB and CB2CB2OAr); 6.90-7.36(m,9fl, aromatic B). 9 |ch2ch(ch3)2 1 1 1 1 1 1 1 1 1 1 1 | 176-8’C 1 | (ethanol)| 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Found: C,65.1; H,7.5; N, 3.IX; required for C^H^CINO^; C, 65.5; B,7.6; Ν, 3.3X; NMR 0.84(d,6B, COCB2CB(CB3)2); 2.04(m,lB, COCB2CH(CB3)2); 2.35(d,2H,COCB2CH(CB3)2); 3.10-3.50(m,4B,CB2NBCB2); 3.66(s,2H ArCB2C0); 3.95-4.10(m,2H,PhOCH2CH); 4.22-4.36(m,3H,CH0H and CB2CH2OAr); 6.92-7.35(m,9H, aromatic H). 1 Example m.p. (solvent) Hicroanalysis/NMR 172-4’C | Found: C,65.8; B.7.8; N,3.4X; (ethanol)| 1 1 1 1 1 1 1 1 1 required for C2^B3^C1NO^: C,66.1; B,7.8; N.3.2X; NMR 0.84(t,3B, CB2CB2CB2CB2C|3); 1.10-1.35(m,4H, CH2CH2CH2CH2CH3); 1.48(quintet, 2H, CBjCBjCBjCBjCBj); 2.46(t,2B, COCH2CH2CH2CH2CH3); 3.12-3.50(m,4H,CH2NHCH2); 3.67(s,2H ArCHjCO); 3.95-4.10(m,2H,PhOCB2CB); 4.24-4.39(m,3B,CB0B and CB2CB2OAr); 6.90-7.36(m,9B, aromatic H) (CH2)5CH3 1 1 1 172-4’C | (ethanol)| 1 Found: C.66.8; B, 8.3; N, 3.OX; required for C^B^CINO^: C,66.7; B,8.0; N, 3.IX; 1 1 NMR 0.85(t,3B, CB2CB2CB2CB2CB2CB3); 1 1 1.15-1.32(m,6B, CB2CB2CB2CB2CB2CB3); 1 1 1.46(quintet,2B,CB2CB2CB2CB2CB2CB3); 1 1 2.46(t,2B,COCB2CB2); 1 1 3.08-3.50(m,4B, CB2NHCB2); 1 1 3.67(s,2B,ArCB2CO); 1 1 3.94-4.10(m,2B PhOCB2CB); 1 1 4.23-4.38(m,3B,CB0B and CB2CH2OAr); 1 1 1 1 6.90-7.36(m,9B, aromatic B) Example| 1 1 r1 1 1 1 m.p. | (solvent) | Microanalysis/NMR 12 1 (ch2)6ch3 i 172-4’C | Pound: C,67.3; H,8.6: N,3.4X; 1 1 1 1 (ethanol)| required for C^HggClNO^: C,67.3; H,8.2; N.3.0X; 1 1 NMR O.86(t,3H, 1 1 1 1 CH2CH2CH2CH2CH2CH2CH3); 1.13-1.33(m,8H, 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 CH2CH2CH2CH2CH2CH2CH3); 1.48(quintet, 2H,CH2CH2CB2CH2CH2CH2CH3); 2.46(t,2H, COCH2CH2CH2-) 3.12-3.53(m,4H, CHjNHCHj); 3.67(s,2H, ArCH2C0); 3.97-4.12(m,2H, PhOCHjCH); 4.26-4.39(m,3H, CHOH and CH2CH20Ar); 6.90-7.36(m,9H, aromatic H) Por convenience the scheme for the preparation of the compounds of Examples 7-12 is set out belov (vherein R is ethyl, n-butyl, isobutyl, n-pentyl, n-hexyl or n-heptyl.

Scheme 2 HO CH2CO-R1 (7) PhOCH2CH(OH)CH2NHCH2CH20—A A-CH^OR1 (9) Footnotes to scheme 2 D. In a manner similar to that described in footnote A to Scheme 1, l-(4-hydroxyphenyl)hexan-2-one vas prepared from commercially available n-butyllithium. 4 E. In a manner similar to that described in footnote B to Scheme 1, l-(4-hydroxyphenyl)-4-methylpentan-2-one, 1-(4-hydroxyphenyl)heptan-2-one, 1-(4-hydroxyphenyl)octan-2-one and l-(4-hydroxyphenyl)nonan-2-one were prepared from the appropriate alkyl bromide.

F. Physical Data for Intermediates in the preparation of the compounds of Examples 8-12.

Example 8 | m.p. | Microanalysis | (solvent) 1 Compound (7) | oil 1 Compound (8) | 77-9eC | Found C, 69.8; H, 7.1; Ν, 3.4X; | (Cyclohexane) | required for C24H29N05:C’ 70.1; 1 1 | H, 7.1; Ν, 3.4X. 1 Example 9 1 1 Compound (7) | oil 1 Compound (8) | 93-5eC | Found C, 70.0; H, 7.2; Ν, 3.4X; | (ethyl acetate/ | required for C^H^NO^: C, 70.1; | cyclohexane) I | H, 7.1; Ν, 3.4X. 1 Example 10 1 1 Compound (7) | Oil 1 Compound (8) | 76-8eC | Found C, 70.8; H, 7.6; Ν, 3.3X; | (ethyl acetate/ | required for C^H^NO^: C, 70.6; | cyclohexane) 1 | H, 7.3; Ν, 3.3X. 1 Example 11 1 1 Compound (7) | Oil 1 Compound (8) ] 81-3eC | Found C, 71.1; H, 7.5; N, 3.IX; | (ethyl acetate/ | required for C26H33NO5: C, 71.1; | cyclohexane) 1 | H, 7.5; Ν, 3.2X. 1 Example 12 Compound (7) Compound (8) 44-6*C 1 | Found C, 77.0; Η, 9.7X; (cyclohexane) | required for C15H?2O2: C, 76.9 | Η, 9.4X. 83-5°C | Found C, 71.3; H, 7.7; N, 3.OX (ethyl acetate/ | required for CjyH^NO^: C, 71. cyclohexane) | H, 7.7; M 1 , 3.IX.

Example 13 (S)-l-[4-(2-(2-Hydroxy-3-phenoxypropylamino)ethoxy)phenyl]pentan-2-one.

In a manner similar to that of Example 7, (S)-5-phenoxymethyl-3-(2-hydroxyethyl)oxazolidin-2-one vas reacted vith 1-(4-hydroxyphenyl)pentan-2-one to give (S)-3-(2-(4-( 2-oxopentyl)phenoxy)ethyl )-5-( phenoxymethyl )oxazolidin-2one vhich vas hydrolysed to the title compound in the form of the hydrochloride; m.p. 166-7*C (ethanol); [α]θ^θ- -11.3* (c «= 1.0, methanol); microanalysis: found C, 64.9; H, 7.5; Ν, 3.7X; required for C22H30C1N04: C’ 64*8; H’ 7,4; N’ 3'4X; O.82(t,3H, CH2CH2CH3); 1.49(sextet, 2H, CH^CHj); 2.44(t,2H,CH2CH2CH3); 3.20-3.48(m,4H,CH2NHCH2); 3.66(s,2H, ArCH2C0); 3.92-4.07(m,2H PhOCH2CH); 4.22-4.38(m,3H, CHOH and CH2CH20Ar); 5.90(1H,OH); 6.90-7.34(m,9H, aromatic H); 9.13 and 9.35(2H, NH2+).

The starting material vas prepared as follows: a) (S)-5-Phenoxymethyloxazolidin-2-one vas prepared from (S)-phenylglycidyl ether and urea using the procedure described by V. J. Kauffman and J. E. Herveh, J. Org. Chem. 1972, 37, 1842-1845. b) Sodium hydride (2.2g of a 50X dispersion in mineral oil) vas added to a stirred solution of 2-bromoethyl acetate (5ml) and (S)-5-phenoxymethyloxazolidin-2-one (8.0g) in anhydrous dimethylformamide (150ml), under argon, at 20®C. When the effervescence had ceased, the reaction mixture vas heated to 45-50°C for 2 hours. The reaction mixture vas cooled, poured into vater t) (750ml) and the product extracted into ethyl acetate (3 x 400ml). The combined ethyl acetate extracts vere vashed vith vater (300ml), dried, and the solvent removed under reduced pressure. The residue vas subjected to chromatography using ethyl acetate in hexane as eluant (gradient elution; 60X to 70X ethyl acetate). The appropriate fractions vere combined to yield (S)-5-phenoxymethyl-3-(2-acetoxyethyl)oxazolidin-2-one (4.6g). c) A solution of the product from b) above (4.5g) and sodium methoxide (l.Og) in methanol (50ml) vas stirred at 20°C for 1 hour. 1° Methanol vas removed by evaporation and the residue partitioned betveen ethyl acetate and vater. The ethyl acetate layer vas separated, dried, and the solvent removed under reduced pressure. The residue vas subjected to chromatography using 2X methanol in dichioromethane as eluant. The appropriate fractions vere combined to yield (S)-5-phenoxymethyl-3-(2-hydroxyethyl)oxazolidin-2-one (2.2g).

Claims (19)

1. 3 vherein R is as hereinbefore defined and R is a protected derivative of -COR 1 : and if necessary thereafter forming an in vivo hydrolysable ester or a pharmaceutically acceptable salt. 10 1-(4-(2-(2-hydroxy-3-phenoxypropylamino)e thoxy)phenyl]hep tan-2-one, l-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]octan-2-one or 1-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]nonan-2-one. 1-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]hexan-2-one, l-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenyl]-4-methylpentan5 2-one, 1-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenylJ-3-methylbutan-2 -one, 1-(4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxyJphenyl]pentan-2-one, (S)-1-(4-(2-(2-hydroxy-3-phenoxypropylamino) ethoxy)phenyl J pentan-2-one, 1-(4-(2-(2-hydroxy-3-phenoxypropylamino) ethoxy)phenyl]propan-2-one,

1. A compound of the formula (I): / \-OCH 2 CH(OH)CH 2 NHCH 2 CH 2 0-r y-C^COR 1 (I) vherein R 1 is hydroxy or (^^alkyl, or an in vivo hydrolysable ester

2. A compound according to claim 1 vherein R^ is hydroxy.

3. A compound according to claim 1 vherein R^ is Cj ^alkyl. 4. 2 4 I 4 Ο (VII) (VIII) vherein R is as hereinbefore defined and L' is a leaving group; or e) deprotecting a compound of the formula (IX): OCH 2 CH(OH)CH 2 NHCH 2 CH (IX) 4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxyJphenylacetic acid or (S)-4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)phenylacetic acid.

4. A compound according to claim 3 vherein R^ is methyl, ethyl, n-propyl, isobutyl, n-butyl or n-hexyl.

5. Vherein R 1 is as hereinbefore defined; or c) for compounds of the formula (I) vherein R^ is hydroxy, hydrolysing a compound of the formula (VI): och 2 ch(oh)ch 2 nhch 2 ch 2 o ch 2 cor 2 (VI) vherein R is a hydrolysable group; 5 or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 vhieh is: 7. \\-0CH 2 CH(0H)CH 2 L (III) (IV) NH 2 CH 2 CH 2 O CH 2 COR vherein R^ is as defined in claim 1 and L is a displaceable group; or b) hydrolysis of a compound of the formula (V):

7. A compound according to any one of claims 1 to 6 vhen in (S)

8. A pharmaceutical composition vhich comprises a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition vhich comprises a compound 10. D) reacting a compound of the formula (VII) vith a compound of the formula (VIII):

10. A process for preparing a compound of the formula (I) or in vivo hydrolysable ester or pharmaceutically acceptable salt thereof as defined in claim 1 vhich comprises: a) reacting a compound of the formula (II) or (III) vith a 20 compound of the formula (IV): 10 absolute configuration at the -CH(OH)- group. 10 5. A compound according to claim 1 vhich is:

11. A compound of the formula (VI): och 2 ch(oh)ch 2 nhch 2 ch 2 o (VI) vherein R is a hydrolysable group.

12. A compound according to claim 11 vherein R is Cj ^alkoxy or amino (-NHp.

13. A compound of the formula (V): (V) or of the formula (IX): ,o-< Ά-ch^r 3 OCH 2 CH(OH)CH 2 NHCH 2 CH 2 O-/ z '\-CH 2 R(IX) vherein R 1 is defined as in claim 1 and R 3 is a protected derivative of -COR 1 .

14. A compound of the formula (XIV): ZCH 2 CH 2 O-^ / />-CH 2 C0R la (XIV) vherein Z is amino, protected amino or a leaving group such as halo or 10 sulphonyloxy and R is Cj ^alkyl vith· the proviso that vhen R is methyl, Z is not amino or protected amino.

15. A compound of the formula (I) given and defined in claim 1, or an in vivo hydrolysable salt or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified. 15 according to claim 7 and a pharmaceutically acceptable carrier. 15 (S)-l-[4-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy) phenyl]propan-2-one, (S)-l-(4-(2-(2-hydroxy-3-phenoxypropylamino) ethoxy) phenyl)butan-2-one,

16. A pharmaceutical composition according to claim 8, substantially as hereinbefore described.

17. A process for preparing a compound of the formula (I) given and defined in claim 1, or an in vivo hydrolysable salt or a pharmaceutically acceptable salt thereof, substantially as hereinbefore described and exemplified.

18. A compound of the formula (I) given and defined in claim 1, or an in vivo hydrolysable salt or pharmaceutically acceptable salt thereof, whenever prepared by a process claimed in a preceding claim.

19. A compound as claimed in any one of claims 11, 13 or 14, substantially as hereinbefore described and exemplified.